The presentation contains the relevant information about the Preformulation Studies done for the pharmaceutical dosage form. It can be useful specially to the students pursuing graduation and post-graduation in pharmacy. It is prepared on the basis of PCI syllabus of M. Pharm. (Pharma Technology and Pharmaceutics).

1. Presentation By :
MAHIRRAO JAYESH ANIL
Roll No.: MPT09
F. Y. M. Pharm.
Department of Pharma Technology
PREFORMULATION STUDIES
R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur

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CONTENTS
 Introduction
 Definition
 Goals
 Areas of Preformulation Research
 Conclusion
 References

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INTRODUCTION:
 PRE FORMULATION: Before the Formulation
 Prior to the development of dosage forms it is essential that they should pertain
properties of the drug molecule.
 This information decides many of the subsequent events and approaches in
formulation development.
 This first learning phase is known as Preformulation.

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DEFINITION:
Preformulation is the first step in the rational
development of dosage forms of a drug substance for
the investigation of physical and chemical properties
of drug substance alone and when combined with
excipients.

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GOALS:
To develop stable, effective and safe dosage forms.
To establish physico-chemical parameters of new drug substance.
To establish the compatibility with the excipient.
To choose correct form of drug substance.

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AREAS OF PREFORMULATION RESEARCH:
A. Organoleptic Properties
B. Bulk Characterization
1. Crystallinity and Polymorphism
2. Hygroscopicity
3. Fine Particle Characterization
4. Bulk Density
5. Powder Flow Properties
C. Solubility Analysis
1. Ionisation Constant (pKa)
2. Partition Coefficient
3. Thermal Effects
D. Stability Analysis
1. Stability in Pharmacological
Formulations
2. Solution Stability
3. Solid State Stability
E. Drug-Excipient Interaction Analysis
1. Differential Scanning Calorimetry
2. X-ray Diffraction
3. Thermogravimetric Analysis

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Properties of compound which can be identified by our sensory organs.
A. ORGANOLEPTIC PROPERTIES
COLOUR ODOUR TASTE
Off-white Pungent Acidic
Cream yellow Sulphurous Bitter
Tan Fruity Bland
Shiny Aromatic Intense
Odourless Sweet
Tasteless
Table 1: Terminologies to describe organoleptic properties

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1. CRYSTALLINITY AND POLYMORPHISM
• Crystal Habit is description of outer appearance of the crystal.
• Crystal Habit depends upon how the internal structure is arranged or present.
Fig. 1: Different shapes of Crystals
B. BULK CHARACTERISTICS

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• Internal Structure is the description of molecular arrangement within the solid.
• Internal Structure may be Crystalline or Amorphous.
PARAMETER CRYSTALLINE FORM AMORPHOUS FORM
1. Structure Definite ordered internal
structure
Do not have any fixed or no
shape internal structure
2. Stability More stable than amorphous
form due to less internal energy
Less stable than crystalline form
due to higher thermodynamic
energy
3. Solubility Less solubility Greater solubility
4. Change to other form Lesser inclination to change its
form during storage
Likely to revert to more stable
form during storage
Table 2: Difference between Crystalline Form and Amorphous Form

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POLYMORPHISM
• Ability of the crystal to exist in more than one form crystalline form
• e.g.: Chloramphenicol palmitate has three polymorphs: Chloramphenicol palmitate A, B, C.
Analytical Methods for Characterization of Solid Forms:
• Microscopy
• Hot Stage Microscopy
• Thermal Analysis
• X-ray Diffraction
Polymorphism
Enantiotropic
(Can reversibly changed into another form
by varying temperature and pressure.
e.g. Sulphur)
Monotropic
(One polymorphic form is unstable at all
temperature and pressure.
e.g. Glyceryl stearate)

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2. HYGROSCOPICITY
• Property of the compound to absorb atmospheric moisture.
Test of Hygroscopicity:
• Bulk drug samples are placed in open containers with thin powder bed to assure maximum
atmospheric exposure.
• These samples are then exposed to range of controlled relative humidity environments
prepared with saturated aqueous solutions.
Moisture Content Analysis can be done by:
• Thermogravimetric Analysis (TGA)
• Karl-Fischer Titration
• Gas Chromatograph
Time of Monitoring:
• For the purpose of Handling: 0-24 hours
• For the purpose of Storage: 0-12 weeks

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3. FINE PARTICLE CHARACTERIZATION
Particle Size, Shape, Surface Morphology can directly affect Bulk flow, Formulation
Homogeneity, Dissolution.
Following parameters should be studied:
1. Particle Size Characterization:
Can be done by
• Light Microscope.
• Coulter Counter
• Sieve Analysis.
2. Surface Area:
Brunauer, Emmett and Teller (BET) Method
3. Surface Morphology:
Scanning Electron Microscope
Fig. 2: Simple representation of Coulter Counter
Fig. 3: Working of Scanning Electron Microscope

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4. BULK DENSITY
Bulk Density:
It is determined by pouring pre-sieved (40 mesh) bulk drug into a graduated cylinder via
funnel and measuring the weight and volume as is it (Bulk volume).
Bulk Density =
Weight of Powder
Bulk Volume
Tapped Density:
It is determined by pouring pre-sieved (40 mesh) bulk drug into a graduated cylinder via
funnel and measuring the weight and volume after tapping until the powder bed has reached a
minimum.
Tapped Density =
Weight of Powder
Tapped Volume

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5. POWDER FLOW PROPERTIES
• Powder flow properties depend on Particle Size, Density, Shape
• Particle flow property can be determined by using Carr’s Compressibility Index
Compressibility =
Tapped Density−Bulk Density
Tapped Density
x 100
% COMPRESSIBILITY FLOWABILITY
5-15 Excellent
12-16 Good
18-21 Fair-passable
23-35 Poor
33-38 Very Poor
<40 Very, very poor
Table 2: Flowability of the Particles w.r.t Compressibility Index

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C. SOLUBILITY ANALYSIS
• Solubility is the maximum quantity of the solute than can dissolve in a certain quantity of
solvent or quantity of solution at a specified temperature of pressure.
• Following solvents are taken for solubility analysis:
i. 0.9 % NaCl
ii. 0.1M HCl
iii. 0.1M NaOH
iv. pH 7.4 buffer
• The drug is dispersed in a solvent. The suspension is agitated at a steady temperature. Samples
of the suspension are withdrawn as a function of time, clarified by centrifugation and assayed
by HPLC, UV, etc.
• Drug concentrations can be determined by following analytical methods:
i. UV-Spectroscopy
ii. HPLC
iii. Gas Chromatography

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1. IONISATION CONSTANT (pKa)
• When a weakly acidic or basic drug partially ionizes in GI fluid, generally unionized
molecules are absorbed quickly.
• Handerson-Hasselbach equation provides an estimate of the ionized and unionized drug
concentrations at particular pH.
• For acidic compounds,
pH = pKa + log
[ionized drug]
[un−ionized drug]
• For basic compounds,
pH = pKa + log
[un−ionized drug]
[ionized drug]
2. PARTITION COEFFICIENT
• It is the ratio of un-ionized drug distributed between the organic phase and aqueous phase at
equilibrium.
• For drug delivery, the lipophilic/hydrophilic balance has been shown to be a contributing factor
for the rate and extent of absorption.
P(o/w) =
C𝑜𝑖𝑙
C𝑤𝑎𝑡𝑒𝑟
equilibrium

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3. THERMAL EFFECTS
• Drugs which are unstable to heat requires refrigerative storage or lyophilisation.
• If it is endothermic ΔH is positive
Increase in Temperature  Increase in Drug Solubility
• If it is exothermic  ΔH is negative
Increase in Temperature  Decrease in Drug Solubility
• For determining ΔH,
ln S = -
ΔH
RT
+ C
S= Molar Solubility at Temperature T
T= Temperature in Kelvin
R= Gas Constant

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1. STABILITY IN TOXICOCOLOGOCAL FORMULATIONS
D. STABILITY ANALYSIS
• A new drug is administered to animals through oral route either by
i. Mixing the drug in the feed
ii. In the form of solution
iii. In the form of suspension in aqueous vehicle
• Feed may contain water, vitamins, minerals (metal ions) enzymes and different functional
groups that may severely reduce the stability of the new drug. So stability study should be
carried out in the feed and at laboratory temperature.
• For solution and suspension, the chemical stability at different temperature and pH should be
check.
• For suspension-state the drug suspension is occasionally shaken to check the dispersibility.
Stability is the extent to which a product retains (throughout its period of storage and use, i.e.,
its shelf life) the same properties that it possessed at the time of its manufacture.

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2. SOLUTION STABLITY
Objective: Identification of conditions necessary to form a stable solution.
Stability of solutions may depend upon:
a. Ionic strength
b. pH
c. Light
a. IONIC STRENGTH
• It is measure of concentration of ions in solution.
• Since most pharmaceutical solutions are intended for parenteral routes of administration,
the pH stability studies should be carried out at a constant ionic strength that is compatible
with body fluids.
• The ionic strength (μ) of an isotonic 0.9 %w/v Sodium chloride solution is 0.15.
μ=
𝟏
𝟐
∑miZi
mi= Molar concentration of the ion
Zi= Valency of the ion

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b. pH STABILITY STUDIES
• Experiments to confirm decay at the extremes of pH and temperature. Stability studies are
carried out at following conditions:
i. 0.1 N HCl solution at 90 oC
ii. Solution in water at 90 oC
iii. 0.1 N NaOH solution at 90 oC
• These experiments are intentionally done to confirm the assay specificity and for maximum
rates for degradation.
• Now aqueous buffers are used to produce solutions with wide range of pH values but with
constant levels of drug concentration, co-solvent and ionic strength.
c. LIGHT
Stability of the drugs checked in by keeping the drug solutions in
i. Clear glass ampoules
ii. Amber colour glass container
iii. Yellow-green colour glass container
iv. Container stored in card-board package or wrapped in aluminium foil (this
acts as control)

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3. SOLID STATE STABLITY
Objective: Identification of stable storage conditions for drug in the solid state and
identification of compatible excipients for formulation.
Characteristics:
• Solid state reactions are much slower, so the rate of appearance of decay production is measured
(not the amount of drug remaining unchanged).
• To determine the mechanism of degradation, Thin Layer Chromatography, Fluorescence or
UV/Visible Spectroscopy may be used.
• To study polymorphic changes DSC or IR Spectroscopy is required.
Procedure:
• Weighed samples are placed in open screw-capped vials and then exposed to a variety of
temperature, humidities and light intensities. After the desired time samples are taken out and
measured by HPLC (5-10 mg), DSC (10-50 mg) IR (2-20 mg).
• To test for surface oxidation samples are stored in large
(25 ml) vials for injection capped with Teflon lined rubber stoppers. These stoppers are
penetrated with needle and headspace is flooded with desired gas. The resulting needle holes
are sealed with was to prevent degassing.
• After fixed time samples are removed and analysed.

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E. DRUG – EXCIPIENT INTERACTION ANALYSIS
• Important for consistent efficacy, safety and stability of drug products.
Incompatibility:
Inactivation of drug through either decomposition or loss by its conversion to less favourable
physical or chemical form.
Importance of Drug-Excipient Interaction analysis:
• Any physical or chemical interaction between drug and excipient can affect stability of drug.
• Helps to avoid surprise problems. Formulator can know possible reactions before formulating
dosage forms.
• Useful in selecting suitable excipients.
Mechanisms of Drug-Excipient Interactions:
• Physical Interactions
• Chemical Interactions
• Biopharmaceutical Interactions

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1. DIFFERENTIAL SCANNING CALORIMETRY (DSC)
• Thermal analysis
• Used for API screening of incompatibilities for over 50 years.
• Difference in ΔH (amount of energy) into a sample and reference material is measured as a
function of temperature as the specimens are subjected to identically steady rise in temperature.
• DSC curves obtained from pure compounds are compared to the curves obtained from 1:1
physical mixture.
• A significant shift in melting point of component or appearance of new peak or disappearance of
existing peak indicates the interaction.
Fig. 5: DSC Thermogram curve of Ketoprofen (KT),
Magnesium Stearate (MS) and
Ketoprofen+Polyvinylpyrrolidone (1:1)
Fig. 4: DSC curve associated with phase transitions

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2. X-RAY DIFFRACTION
• Useful in interactions occur during processes like compression, wet granulation, etc. and brings
change in crystallinity/amorphosity and polymorphic forms of API in the presence of excipients.
• When an X-ray beam falls on a powder the beam is diffracted and peaks are observed.
• Interpretation: The peaks or finger prints observed indicates crystalline powder. No peaks
indicates amorphous forms.
Fig. 7: X-ray diffractogram of polyvinylpyrrolidone
(PVP), Ketoprofen (KT) and
Ketoprofen+Polyvinylpyrrolidone (1:1)
Fig. 6: Schematic diagram of Powdered X-ray Diffraction

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3. THERMOGRAVIMETRIC ANALYSIS (TGA)
• Measures change in weight of sample as a function of time.
• Sample is heated in inert gas environment at controlled rate.
• The temperature is increased at constant rate for a known initial weight of the substance and
changes in weights are recorded as a function of temperature at different time interval.
Fig. 9: Thermogram of Diclofenac Sodium, Magnesium
Stearate and Diclofenac Sodium+Magnesium Stearate (1:1)
Fig. 8: Block Diagram of TGA Instrument

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CONCLUSION
• Preformulation studies have a significant part to play in anticipating formulation problems
and identifying logical paths in developing dosage forms.
• Preformulation studies on a new drug molecule provide useful information for subsequent
formulation of physico-chemically stable and biopharmaceutically suitable dosage form.
• Preformulation work is the the foundation of developing efficacious and economical
formulations.

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1. Leon Lachman, Herbert Lieberman, Joseph Kanig, The Theory and Practice of Industrial Pharmacy,
Varghsese Publising House, Third Edition, 2008, pp. 176-194.
2. B. Prakash Rao, S. Rajarajan, Beny Baby, Industrial Pharmacy-I, Nirali Prakashan, First Edition,
2019, pp. 1.1-1.30.
3. Prasanna Kumar Desu, G. Vaishnavi, K, Divya, U. Lakshmi, An Overview on Preformulation
Studies, Indo American Journal of Pharmaceutical Sciences, Vol. 2 (10), 2015, pp. 1399-1407.
4. Priyanka Patel, Kajal Ahir, Vandana Patel, Drug-Excipient Compatibility Studies: First step for
dosage form development, The Pharma Innovation Journal, Vol. 4 (5), 2015, pp. 14-20.
5. Bapi Gorain, Hira Chaoudhury, Manisha Pandey, Drug-Excipient Interaction and Incompatibilities,
Dosage Form Design Parameters, 2018, pp. 363-402.
REFERENCES

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THANK YOU
FOR YOUR
ATTENTION!!!